The Use Of Selective HDAC6

The Use Of Selective HDAC6

In CLL, malignant B cells evade immune detection and lead to immune suppression. Recently, histone deacetylases (HDACs) have been shown to play an active role in the regulation of pathogenesis and immune-related pathways in CLL, although their role in B-cell receptor signaling remains unknown. Previously, aberrant overexpression of HDAC6 has been demonstrated in CLL cell lines and patient samples, and the authors sought to understand the mechanistic role of HDAC6 in CLL.

In collaboration with Acetylon scientists, the authors demonstrated that selective HDAC6 inhibition in CLL cell lines resulted in dose-dependent reductions in IL-10, a cytokine that regulates cell proliferation in CLL, as well as dose-dependent increases in cell death and a synergistic reduction in cell viability in combination with the BTK inhibitor, ibrutinib. Genetic knockdown of HDAC6 in CLL cells reduced expression of PD-L1 and other immune checkpoint markers, while increasing markers related to antigen presentation, including MHC II. Using an animal model of CLL, the authors then demonstrated with systemic administration of a selective HDAC6 inhibitor, a reduction in disease burden and increased survival in parallel with diminished expression of immune checkpoint markers on T-cells and B-cells, as well as a reduction in the number of immunosuppressive T-cells (Tregs).

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